Comparative Pharmacokinetic Study for Linezolid and Two Novel Antibacterial Oxazolidinone Derivatives in Rabbits: Can Differences in the Pharmacokinetic Properties Explain the Discrepancies between Their In Vivo and In Vitro Antibacterial Activities?

This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents-PH027 and PH051-in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 ± 6.3, 68.7 ± 12.1 and 175 ± 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32-34%, 37-38% and 90-91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability.

A validated UPLC-MS/MS method for the analysis of linezolid and a novel oxazolidinone derivative (PH027) in plasma and its application to tissue distribution study in rabbits.

OBJECTIVES: Linezolid is the first approved oxazolidinone antibacterial agent, whereas PH027 is a novel compound of the same class that exhibits good in vitro antibacterial activity. The objective of this study was to develop an UPLC-MS/MS assay for the analysis of linezolid and PH027 in plasma and to apply the method for comparative pharmacokinetic and tissue distribution studies of both compounds. METHOD: Plasma samples and calibrators were extracted with diethyl ether after addition of the internal standard solution. After evaporation of the ether layer, the residue was reconstituted in mobile phase and injected into UPLC-MS/MS. The mobile phase consisted of 2mM ammonium acetate buffer solution and acetonitrile (70:30) at a flow rate of 0.2ml/min. Separation was achieved using UPLC BEH C18 column, and quantitative determination of the analytes was performed using multiple-reaction monitoring (MRM) scanning mode. The method was validated by analyzing quality control tissue homogenate samples, and was applied to analyze tissue homogenate samples obtained following IV injections of linezolid and PH027 in rabbits. RESULTS: The developed UPLC-MS/MS method was linear in the concentration range of 50-5000ng/ml. Validation of the method proved that the method's precision, selectivity and stability were all within the acceptable limits. Linezolid and PH027 concentrations were accurately determined in the quality control tissue homogenate samples, and analysis of samples obtained following IV administration of the two compounds showed that the tissue to plasma concentration ratio of PH027 was higher than that of linezolid probably due to its higher lipophilicity. CONCLUSIONS: The developed UPLC-MS/MS method for the analysis of linezolid and PH027 in rabbit's plasma can accurately determine the concentrations of these compounds in different tissues.

Coumarin Derivatives as Anti-inflammatory and Anticancer Agents.

BACKGROUND: Inflammation substantially contributes to the development and progression of malignancies. cancer-related inflammation, has been proposed to promote tumor progression and serve as the seventh hallmark of tumor. Tumor microenvironment, products of inflammatory cells influence almost every aspect of tumorigenesis and tumor progression. OBJECTIVE: The aim of this study was to design and evaluate drug candidates targeting cancer-related inflammation. METHOD: A series of 4-hydroxy- 3-(2- (2-[2- [(substituted phenyl)methylidene]hydrazin-1- yl]-1,3- thiazol-5- yl)-1- phenylethyl)-2H-chromen- 2-one (4a-j) were synthesized for its potential activity towards COX-2 inhibition and anticancer activity against MCF-7 and EAC cell lines. The structures of the synthesized compounds were elucidated using spectral data. Docking study was also performed to determine the probable binding mode of the compounds into the active site. RESULTS: Compound 4b showed significant anti-inflammatory and anticancer activity. CONCLUSION: According to the results, it was concluded that designing compounds targeting cancer-related inflammation could be helpful in developing promising drug candidates for the treatment of cancer.